Deferasirox pharmacokinetics in patients with adequate versus inadequate response.

Tens of thousands of transfusion-dependent (eg, thalassemia) patients worldwide suffer from chronic iron overload and its potentially fatal complications. The oral iron chelator deferasirox has become commercially available in many countries since 2006. Although this alternative to parenteral deferoxamine has been a major advance for patients with transfusional hemosiderosis, a proportion of patients have suboptimal response to the maximum approved doses (30 mg/kg per day), and do not achieve negative iron balance. We performed a prospective study of oral deferasirox pharmacokinetics (PK), comparing 10 transfused patients with inadequate deferasirox response (rising ferritin trend or rising liver iron on deferasirox doses > 30 mg/kg per day) with control transfusion-dependent patients (n = 5) with adequate response. Subjects were admitted for 4 assessments: deferoxamine infusion and urinary iron measurement to assess readily chelatable iron; quantitative hepatobiliary scintigraphy to assess hepatic uptake and excretion of chelate; a 24-hour deferasirox PK study following a single 35-mg/kg dose of oral deferasirox; and pharmacogenomic analysis. Patients with inadequate response to deferasirox had significantly lower systemic drug exposure compared with control patients (P < .00001). Cmax, volume of distribution/bioavailability (Vd/F), and elimination half-life (t(1/2)) were not different between the groups, suggesting bioavailability as the likely discriminant. Effective dosing regimens for inadequately responding patients to deferasirox must be determined. This trial has been registered at http://www.clinicaltrials.gov under identifier NCT00749515.

Oral chelation: should it be used with young children?

Deferasirox, the only oral iron chelator approved in the US and Canada, achieved a pediatric label indication down to 2 years of age. FDA-mandated post-marketing safety surveillance in children under age 6 is ongoing. We wish to raise a non-safety-related concern with deferasirox chelation in very young children (2-5 years old). Specifically, the circumstances required for reliable daily ingestion of deferasirox do not mesh well with the developmental characteristics common in young children, which may limit adherence and cause parental distress. We review developmental challenges associated with oral chelation in this age group and provide suggestions to improve adherence in this population.

Practical implications of liver and heart iron load assessment by T2*-MRI in children and adults with transfusion-dependent anemias.

This study examined the relationship between hepatic and myocardial iron concentration, assessed by T2*-MRI in 66 patients (3-82 years) with transfusion-dependent anemias and thalassemia intermedia, to determine whether hepatic iron levels alone suffice for chelation adjustments. We found a poor correlation between hepatic and myocardial iron (r = 0.10, P = 0.43) and identified a subgroup (14%) with increased myocardial iron without a matched degree of hepatic hemosiderosis. Left ventricular ejection fraction was insensitive for detecting elevated myocardial iron. These findings were present in both adult and pediatric patients. We recommend therapeutic monitoring of iron burden by evaluation of both liver and myocardial iron with T2*-MRI.